Biomedical subjects
Publications and source records attributed to D J Graham.
We investigate the thermal denaturation of DNA hairpins using molecular dynamics simulations of a simple model describing the molecule at a scale of a nucleotide. The model allows us to analyze the different interacting features that determine how an hairpin opens, such as therole of the loop and the properties intrinsic to the stem.
Recently synthesized (Winter, R.; Nixon, P. G.; Gard, G. L.; Radford, D. H.; Holcomb, N. R.; Grainger, D. W. J. Fluorine Chem. 2001, 107, 23-30) SF5-terminated perfluoroalkyl thiols (SF5(CF2)nCH2CH2SH, where n = 2, 4, and 6) and a symmetric SF5-terminated dialkyl disulfide ([SF5-CH=CH-(CH2)8-S-]2) were assembled as thin films chemisorbed onto gold surfaces. The adsorbed monolayer films of these SF5-containing molecules on polycrystalline gold were compared using ellipsometry, contact angle, X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and infrared spectroscopy (FTIR) surface analytical methods. The resulting SF5-dialkyl disulfide monolayer film shows moderate angle dependence in depth-dependent XPS analysis, suggesting a preferentially oriented film. The SF5-terminated perfluoroalkyl thiols exhibit angular-dependent XPS compositional variance depending on perfluoroalkyl chain length, consistent with improved film assembly (increasingly hydrophobic, fewer defects, and more vertical chain orientation increasing film thickness) with increasing chain length. Tof-SIMS measurements indicate that both full parent ions for these film-forming molecules and the unique SF5 terminal group are readily detectable from the thin films without substantial contamination from other adsorbates.
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CONTEXT: Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000. OBJECTIVE: To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone. DESIGN, SETTING, AND PARTICIPANTS: Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations. MAIN OUTCOME MEASURES: Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims. RESULTS: Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use. CONCLUSIONS: The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.
Cigarette smoking is among the leading risk factors in the etiology of atherosclerotic vascular disease. The mechanism, however, that links cigarette smoking to an increased incidence of atherosclerosis is poorly understood. Endothelial cell (EC) integrity is critical in preventing vascular lesion formation, and after a loss of EC integrity reendothelialization must be rapid and complete. We therefore investigated whether cigarette smoke affected the ECs ability to migrate or altered the intracellular signals generated during migration. The DMSO-soluble fraction of cigarette smoke condensate (CSC), derived from the standard research cigarette, was tested on cultured ECs (HUVEC) derived from human umbilical vein. The addition of CSC caused a dose-dependent decrease in the ability of EC to migrate as measured over a 24-h time period. Nicotine and cadmium sulfate, two constituents of cigarette smoke, individually or in combination, had no effect on migration. Examination of the tyrosine phosphorylation state of various intracellular proteins by Western blot analysis showed that CSC caused the hyperphosphorylation of a 130-kDa protein. In addition, other intracellular proteins showed changes in their phosphorylation states after CSC addition. These results support the hypothesis that CSC is detrimental to normal EC function in maintaining vascular integrity and suggest that smokers are more likely to develop complications of vascular disease due to delayed or incomplete reendothelialization as a consequence of decreased EC migration.
The surfaces of six biologically interesting calcium phosphate (CaP) phases (hydroxyapatite, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, monobasic calcium phosphate, beta-tribasic calcium phosphate, octacalcium phosphate) have been examined by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). The intensity of an O(1s) shake-up satellite correlates with the phosphate oxygen content. Together with the Ca/P and O/Ca XPS peak ratios, this feature helps provide identification of the CaP phase(s) present in the surface of unknown samples and establish their mole fractions, as proven with a bone sample. Contributions from carbonate impurities can be quantified using its C(1s) peak at 279.9 eV and subtracted from the O(1s) line shape to aid identification. Principal component analysis (PCA) has been applied successfully to analyze TOF-SIMS spectra of these six CaP phases. Multivariate analysis can help differentiate these CaP phases using the first two PCs, which are dominated by the relative intensities of only a few key ions: PO3-, O-, Ca+, CaOH+, PO2-, and OH-.
OBJECTIVE: The goal of this study was to determine the prevalence of Clostridium difficile diarrhea (CDD) and the risk for CDD associated with different oral antibiotics commonly used in the ambulatory care setting. METHODS: The prevalence of CDD was determined for enrollees in 4 UnitedHealth Group-affiliated health plans between January 1, 1992, and December 31, 1994. Cases were identified based on the presence of an inpatient or outpatient claim with a primary diagnosis of diarrhea, a pharmacy claim for a prescription drug used to treat CDD, or a physician or facility claim for the C. difficile toxin test, and were confirmed using full-text medical records. Within a retrospective cohort design, periods of risk for CDD were defined on the basis of duration of antibiotic therapy. To control for potential selection bias created by heterogeneous rates of C. difficile testing and to limit confounding due to multiple antibiotic exposures, we used a nested case-control design, restricting eligibility to subjects who underwent screening for C. difficile and who had been exposed to only 1 antibiotic risk period with a single antibiotic. RESULTS: The global prevalence of CDD in 358,389 ambulatory care enrollees was 12 per 100,000 person-years. In the nested case-control study, after controlling for other risk factors, 2 antibiotics demonstrated an increased association with CDD: cephalexin (odds ratio [OR] = 7.5, 95% CI = 1.8 to 34.7) and cefixime (OR = 6.4, 95% CI = 1.2 to 39.0). CONCLUSIONS: Although CDD is thought to occur primarily in hospitalized patients, it was found to be present in an ambulatory care population, but at a low frequency. In this population, it appeared to be associated with 2 cephalosporins but not with other types of antibiotics usually linked with nosocomial CDD. Because the frequency of C. difficile testing was shown to be more common with high-risk antibiotics, CDD may be underdiagnosed in the ambulatory care setting.
OBJECTIVE: To determine whether the severity of valvulopathy was associated with the dosage of fenfluramine taken by fenfluramine-phentermine users with valvulopathy. DESIGN: Out of 105 suspected valvulopathy case reports received by the US Food and Drug Administration (FDA) among fenfluramine-phentermine users, 74 patients meeting FDA case definition for valvulopathy were included in this study. Patients with severe valvulopathy were classified as those either undergoing valve replacement surgery or having severe aortic or mitral regurgitation; all other patients were considered to have less severe valvulopathy. RESULTS: The proportion with severe valvulopathy increased from 20-66% with increasing fenfluramine dosage from </=40 mg/d to >/=60 mg/d. Compared with patients taking<40 mg/d fenfluramine, patients taking >/=60 mg/d had an adjusted odds ratio of 9.2 (95% confidence interval=2.1-40.8) for severe valvulopathy. CONCLUSION: Compared to patients with less severe valvulopathy, those with severe valvulopathy were substantially more likely to have taken >/=60 mg/d fenfluramine.
Short courses of oral corticosteroids are widely used to treat asthma. The objective of this study was to assess if one course of oral corticosteroids increases asthmatic children's risk for infections treated with outpatient antibiotics. Using New York State Medicaid claims data on asthmatic children 2-15 years old, we made cohorts of oral corticosteroid users and nonusers. We determined the percentage of children who filled antibiotic prescriptions in the 30 days after index dates. Index dates were dates oral steroids were started (for steroid users) or matched dates (for nonusers). Odds ratios were adjusted for age, month of index date, and prior antibiotic use. Among children not receiving antibiotics on index dates, antibiotic prescriptions were filled in the next 30 days for 438 (20%) of 2145 steroid nonusers and 130 (19%) of 698 steroid users (p=0.30); compared to nonusers, steroid users had an adjusted odds ratio of subsequent antibiotic use of 0.92 (95% confidence interval [CI] 0.73-1.15). Among children receiving antibiotics on index dates, antibiotic prescriptions were filled in the next 30 days for 116 (26%) of 451 steroid nonusers and 50 (19%) of 260 steroid users (p=0.05); compared to nonusers, steroid users had an adjusted odds ratio of subsequent antibiotic use of 0.65 (95% CI 0.53-0.97). We conclude that one course of oral corticosteroids does not increase asthmatic children's risk for infections treated with outpatient antibiotics.
Concurrent infection is a risk factor for abdominal wound dehiscence. We reviewed our experience with fascial dehiscence to determine the incidence and to identify prognostic factors for associated intra-abdominal infection. Over a 7-year period, 107 patients with abdominal wound dehiscence were identified. Seventeen were managed nonoperatively, and 90 underwent exploratory laparotomy, 43 of whom had no intra-abdominal pathology and 47 of whom had intra-abdominal infections. Demographic factors, comorbid diseases, and potential indicators of systemic infection did not distinguish patients with intra-abdominal infection from those without. Patients with an intra-abdominal infection were more likely to have undergone an emergency operation (74% vs 48%; P < 0.02), an operation on the colon (55% vs 25%; P < 0.005), or an operation with a higher wound classification (P < 0.02). Mortality was higher in patients with intra-abdominal infection than in those without (44% vs 20%; P < 0.02). Wound dehiscence after emergent operations, and operations with a higher wound classification, especially those involving the colon, should raise concern for intra-abdominal infection. Thorough abdominal exploration should be performed at the time of dehiscence repair. Before nonoperative management is chosen, intra-abdominal infection should be excluded.
Adrenal masses are identified incidentally on up to 1.5% of all abdominal CT scans. The appropriate evaluation and management of these "incidentalomas" remains controversial and centers on questions of function and potential for malignancy. Functional evaluation includes consideration of the diagnoses of aldosteronoma, pheochromocytoma, and corticosteroid-producing adenoma. Potential for malignancy can be evaluated using a number of imaging modalities, although none is diagnostic. Size remains one of the best criteria for assessing potential for malignancy.
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Counts of the number of publication titles containing the search truncation "pinea*" were compiled via Current Contents over the time period 1978-1994. These counts and their time dependence were examined for autocorrelations and frequency spectral components. Such analyses were carried out irrespective of either author, research laboratory, funding, or other factors. Interestingly, the results show the research publication rate in pineal studies to be linked to community history. In particular, the interactions affecting output among community members operate on a few characteristic time scales ranging from one to several years.
The US Food and Drug Administration (FDA)'s Spontaneous Adverse Experience Reporting System is a computerized database with over one million adverse drug experience (ADE) reports. In 1992, the FDA received over 100,000 ADE reports and pharmacists were major contributors to these reports. In 1993, the FDA launched MEDWatch, a new initiative to enhance direct reporting of adverse events by health professionals. thus far, majority of reports to MEDWatch are from pharmacists. Drug regulatory agencies of some countries do not accept reports submitted by pharmacists. We performed a study to assess the quality of information in ADE reports submitted directly to the FDA by pharmacists and physicians and compared that with manufacturer-channelled 15-day reports. We evaluated 589 ADE reports with serious outcomes associated with nine new molecular entities. Data were analysed using Epi Info. Our results showed no substantial difference in a subjective assessment of the quality of information in the reports submitted by pharmacists or physicians, irrespective of whether these reports were submitted directly or via manufacturers. This study suggests that reports from hospital pharmacists are valuable and of comparable quality. We believe that all health professionals contribute to the success of FDA's MEDWatch programme and thereby play an important part in protecting public health by promptly reporting serious adverse events.
BACKGROUND: Squamous cell carcinoma (SCC) of the breast is rare. It remains unclear whether a "pure" form of SCC exists or if all known cases actually represent an extreme form of squamous metaplasia within adenocarcinoma. Due to its rarity and controversy over its definition, there are no good data on appropriate management and prognosis. METHODS: All cases of breast carcinoma indexed at our institution were reviewed to identify seven cases where squamous metaplasia was a significant component of the pathologic diagnosis. Slides and electron micrographs were reviewed by a single pathologist. Clinical information was obtained from medical records. RESULTS: These cases support the concept of a disease continuum with varying degrees of squamous metaplasia. When tumors identified as "pure" SCC on light microscopy are subjected to ultrastructural analysis, either separate squamous and glandular cells are present or both histologic features are noted to coexist in the same cell. CONCLUSIONS: Identification of "pure" cases of SCC appears clinically unimportant. All patients presented with advanced disease, thus necessitating aggressive management regardless of histology. Mastectomy was performed due to large tumor size and adjuvant chemotherapy given rather than hormones because of receptor negativity. The mixed histology should direct future drug choice. The role of radiation remains unclear.
Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.
Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture. We now report the characterization of resistant variants isolated from patients undergoing therapy with the protease inhibitor MK-639 (formerly designated L-735,524). Five of these variants, isolated from four patients, exhibited cross-resistance to all members of a panel of six structurally diverse protease inhibitors. This suggests that combination therapy with multiple protease inhibitors may not prevent loss of antiviral activity resulting from resistance selection. In addition, previous therapy with one compound may abrogate the benefit of subsequent treatment with a second inhibitor.